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Molecular and Cellular Biology

Kumar Abhishek, Abul Hasan Sardar, Sushmita Das, Ashish Kumar, Ayan Kumar Ghosh, Ruby Singh, Savita Saini, Abhishek Mandal, Sudha Verma, Ajay Kumar, Bidyut Purkait, Manas Ranjan Dikhit, Pradeep Das
Leishmania donovani transformation to amastigote from promastigote during mammalian host infection; displays the immense adaptability of the parasite to survive under stress. Induction of translation initiation factor 2-alpha (eIF2α) phosphorylation by stress specific eIF2α kinases is the basic stress perceiving signal in eukaryotes to counter stress. Here, we demonstrate that elevated temperature and acidic pH; induces phosphorylation of Leishmania donovani eIF2α (LdeIF2α). The in-vitro inhibition experiments suggest interference of LdeIF2α phosphorylation under elevated temperature and acidic pH debilitates parasite differentiation and reduces parasite viability (P< 0...
October 10, 2016: Molecular and Cellular Biology
Young Bong Choi, Noula Shembade, Kislay Parvatiyar, Siddharth Balachandran, Edward William Harhaj
The host response to RNA virus infection consists of an intrinsic innate immune response and the induction of apoptosis as mechanisms to restrict viral replication. The mitochondrial adaptor molecule MAVS plays critical roles in coordinating both virus-induced type I interferon production and apoptosis; however, the regulation of MAVS-mediated apoptosis is poorly understood. Here, we show that the adaptor protein TAX1BP1 functions as a negative regulator of virus-induced apoptosis. TAX1BP1-deficient cells are highly sensitive to apoptosis in response to infection with the RNA viruses vesicular stomatitis virus and Sendai virus and transfection with poly(I:C)...
October 10, 2016: Molecular and Cellular Biology
Sang C Lee, Jack Zhang, Josh Strom, Danzhou Yang, Thai Nho Dinh, Kyle Kappeler, Qin M Chen
Inhibition of protein synthesis serves as a general measure of cellular consequence to chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in 5' Untranslated Region (5' UTR) of NRF2 mRNA, as measured by Circular Dichroism, Nuclear Magnetic Resonance, and Dimethylsulfate Footprinting...
October 10, 2016: Molecular and Cellular Biology
Risa Mukai, Takayuki Ohshima
Human T-cell leukemia virus type1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine-zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of myeloid cell leukemia-1 (MCL1) is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expression and suppressed MCL-mediated release of cytochrome c from the mitochondria...
October 3, 2016: Molecular and Cellular Biology
Martin G Sauer, Jessica Herbst, Ulf Diekmann, Christopher E Rudd, Christian Kardinal
The clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft versus host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed to the activation of integrins such as LFA-1 is poorly understood. Here, we identify a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting...
October 3, 2016: Molecular and Cellular Biology
Boris Topolski, Visnja Jakopec, Natascha A Künzel, Ursula Fleig
Chromosome transmission fidelity during mitosis is of critical importance for the fitness of an organism as mistakes will lead to aneuploidy, which has a causative role in numerous severe diseases. Proper segregation of chromosomes depends on interdependent processes at the microtubule-kinetochore interface and the spindle assembly checkpoint. Here we report the discovery of a new element essential for chromosome transmission fidelity that implicates inositol pyrophosphates (IPPs) as playing a key role in this process...
October 3, 2016: Molecular and Cellular Biology
Kwang-Jin Cho, Darren E Casteel, Priyanka Prakash, Lingxiao Tan, Dharini van der Hoeven, Angela A Salim, Choel Kim, Robert J Capon, Ernest Lacey, Shane R Cunha, Alemayehu A Gorfe, John F Hancock
K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells activated PKG2 selectively co-localizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP kinase and requires eNOS and soluble guanylyl-cyclase. Phosphorylated K-Ras re-organizes into distinct nanoclusters that retune signal output...
October 3, 2016: Molecular and Cellular Biology
Manoj Prasad, Anna N Walker, Jasmeet Kaur, James L Thomas, Shirley A Powell, Amit V Pandey, Randy M Whittal, William E Burak, Guy Petruzzelli, Himangshu S Bose
The acute response to stress consists of a series of physiological programs to promote survival by generating glucocorticoids and activating stress-response genes that increase the synthesis of many chaperone proteins specific to individual organelles. In the endoplasmic reticulum (ER), short-term stress triggers activation of the unfolded protein response (UPR) module that either leads to neutralization of the initial stress or adaption to it; chronic stress favors cell death. UPR induces expression of the transcription factor, C/EBP homology protein (CHOP), and its deletion protects against the lethal consequences of prolonged UPR...
October 3, 2016: Molecular and Cellular Biology
Anne-Marie Landry-Voyer, Sarah Bilodeau, Danny Bergeron, Kiersten L Dionne, Sarah A Port, Caroline Rouleau, François-Michel Boisvert, Ralph H Kehlenbach, François Bachand
The protein arginine methyltransferase 3 (PRMT3) forms a stable complex with the 40S ribosomal protein S2 (RPS2) and contributes to ribosome biogenesis. However, the molecular mechanism by which PRMT3 influences ribosome biogenesis and/or function still remains unclear. Using quantitative proteomics, we identified the human Programmed Cell Death 2-like (PDCD2L) as a novel PRMT3-associated protein. Our data suggest that RPS2 promotes the formation of a conserved extra-ribosomal complex with PRMT3 and PDCD2L...
October 3, 2016: Molecular and Cellular Biology
Kimberly Maxfield, Jennifer Macion, Hariprasad Vankayalapati, Angelique W Whitehurst
Triple negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery and radiation. To identify new intervention targets in TNBC, we used large-scale, loss of function screening to identify molecular vulnerabilities among different oncogenomic backgrounds...
October 3, 2016: Molecular and Cellular Biology
Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto
The transcription factor Nrf2 (NF-E2-related-factor-2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein-1), an adaptor for a Cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown...
October 3, 2016: Molecular and Cellular Biology
Chinh Q Hoang, Michael A Hale, Ana Azevedo-Pouly, Hans P Elsässer, Tye G Deering, Spencer G Willet, Fong C Pan, Mark A Magnuson, Christopher V E Wright, Galvin H Swift, Raymond J MacDonald
Maintenance of cell-type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. RNA-Seq and ChIP-Seq results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR)...
October 3, 2016: Molecular and Cellular Biology
Donghyun Joo, Yong Tang, Marzenna Blonska, Jianping Jin, Xueqiang Zhao, Xin Lin
Cell death and survival signaling pathways have opposed but fundamental functions for various cellular processes and crosstalk to each other to maintain cell homeostasis. Here, we report the novel mechanism between these two pathways through the cleavage of RNF31 by caspases. RNF31, a component of the linear ubiquitin chain assembly complex (LUBAC), regulates cell survival by inducing linear ubiquitination of NF-κB signaling components. We found that RNF31 is cleaved in apoptosis condition through various stimulations...
September 26, 2016: Molecular and Cellular Biology
Lei Fang, Danqi Chen, Clinton Yu, Hongjie Li, Jason Brocato, Lan Huang, Chunyuan Jin
Acrolein is a major component of cigarette smoke and cooking fumes. Previously, we reported that acrolein compromises chromatin assembly; however, underlying mechanisms have not been defined. Here, we report that acrolein reacts with lysine residues including lysines 5 and 12 on histone H4 in vitro and in vivo, sites important for chromatin assembly. Acrolein-modified histones are resistant to acetylation, suggesting that the reduced H4K12 acetylation following acrolein exposure is likely due to the formation of acrolein-histone lysine adducts...
September 26, 2016: Molecular and Cellular Biology
Lluís Cordón-Barris, Sònia Pascual-Guiral, Shaobin Yang, Lydia Giménez-Llort, Silvia Lope-Piedrafita, Carlota Niemeyer, Enrique Claro, Jose M Lizcano, Jose R Bayascas
The phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway plays essential roles during neuronal development. The 3-phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating twenty three kinases of the AGC family including Akt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate and activate most of these kinases, with the exception of Akt. We exploited this differential mechanism of regulation by generating neuronal-specific conditional knock-in mice expressing the mutant form of PDK1 L155E in which the substrate-docking site binding motif, termed the PIF-pocket, was disrupted...
September 19, 2016: Molecular and Cellular Biology
George Fullbright, Halley B Rycenga, Jordon D Gruber, David T Long
Inter-strand crosslinks (ICLs) are extremely toxic DNA lesions that create an impassable roadblock to DNA replication. When a replication fork collides with an ICL, it triggers a damage response that promotes multiple DNA processing events required to excise the crosslink from chromatin and resolve the stalled replication fork. One of the first steps in this process involves displacement of the CMG replicative helicase (comprised of Cdc45, MCM2-7, and GINS), which obstructs the underlying crosslink. Here we report that the p97/Cdc48/VCP segregase plays a critical role in ICL repair by unloading the CMG complex from chromatin...
September 19, 2016: Molecular and Cellular Biology
Sezin Dagdeviren, Dae Young Jung, Eunjung Lee, Randall H Friedline, Hye-Lim Noh, Jong Hun Kim, Payal R Patel, Nicholas Tsitsilianos, Andrew V Tsitsilianos, Duy A Tran, George H Tsougranis, Caitlyn C Kearns, Cecilia P Uong, Jung Yeon Kwon, Werner Muller, Ki Won Lee, Jason K Kim
Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M(IL10)). After 16 weeks of high-fat diet (HFD), M(IL10) mice became markedly obese but showed improved insulin action as compared to wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle...
September 19, 2016: Molecular and Cellular Biology
Mei Jiang, Ana Azevedo-Pouly, Tye G Deering, Chinh Q Hoang, Daniel DiRenzo, David A Hess, Stephen F Konieczny, Galvin H Swift, Raymond J MacDonald
Much remains unknown regarding the regulatory networks formed by transcription factors in mature, differentiated mammalian cells in vivo, despite many studies of individual DNA-binding transcription factors. We report a constellation of feed-forward loops formed by the pancreatic transcription factors MIST1 and PTF1 that govern the differentiated phenotype of the adult pancreatic acinar cell. PTF1 is an atypical basic helix-loop-helix transcription factor complex of pancreatic acinar cells and critical to acinar cell fate specification and differentiation...
September 19, 2016: Molecular and Cellular Biology
David A Hess, Katherine M Strelau, Anju Karki, Mei Jiang, Ana C Azevedo-Pouly, Ann-Hwee Lee, Tye G Deering, Chinh Q Hoang, Raymond J MacDonald, Stephen F Konieczny
Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator...
September 19, 2016: Molecular and Cellular Biology
Heather L Hayes, Lu Zhang, Thomas C Becker, Jonathan Haldeman, Samuel B Stephens, Michelle Arlotto, Larry G Moss, Christopher B Newgard, Hans E Hohmeier
The homeodomain transcription factor, Pdx-1, has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under control of a β-cell-specific promoter (RIP) stimulates proliferation of both α- and β-cells, and overexpression of Pdx-1 in islets separated by a transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets...
September 12, 2016: Molecular and Cellular Biology
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